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WO2008130614A3 - Selective and dual-action p53/mdm2/mdm4 antagonists - Google Patents

Selective and dual-action p53/mdm2/mdm4 antagonists Download PDF

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Publication number
WO2008130614A3
WO2008130614A3 PCT/US2008/004993 US2008004993W WO2008130614A3 WO 2008130614 A3 WO2008130614 A3 WO 2008130614A3 US 2008004993 W US2008004993 W US 2008004993W WO 2008130614 A3 WO2008130614 A3 WO 2008130614A3
Authority
WO
WIPO (PCT)
Prior art keywords
mdm2
mcr
compounds
mdm4
disrupt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2008/004993
Other languages
French (fr)
Other versions
WO2008130614A2 (en
Inventor
Alexander Doemling
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Pittsburgh
Original Assignee
University of Pittsburgh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Pittsburgh filed Critical University of Pittsburgh
Publication of WO2008130614A2 publication Critical patent/WO2008130614A2/en
Publication of WO2008130614A3 publication Critical patent/WO2008130614A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4703—Regulators; Modulating activity
    • G01N2333/4704—Inhibitors; Supressors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4748—Details p53
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/02—Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Cell Biology (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

A fragment-based strategy, involving 'multicomponent reaction chemistry' (MCR), can identify novel chemotypes that disrupt the p53/MDM2 or p53/MDM4 complex employs. This approach uses high resolution structural information to delineate the region of a first protein or a ligand that is nestled within the binding pocket of a second target protein. The identified region is imported into a database containing MCR scaffolds to generate a virtual library of compounds, which subsequently are docked into the binding pocket of the target protein. Results from docking then are used to select compounds for synthesis and screening. A complementary, NMR-based methodology allows for screening the ability of compounds, selected using MCR, to disrupt the p53/MDM2 or p53/MDM4 complex.
PCT/US2008/004993 2007-04-20 2008-04-18 Selective and dual-action p53/mdm2/mdm4 antagonists Ceased WO2008130614A2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US90790207P 2007-04-20 2007-04-20
US60/907,902 2007-04-20
US96051607P 2007-10-02 2007-10-02
US60/960,516 2007-10-02

Publications (2)

Publication Number Publication Date
WO2008130614A2 WO2008130614A2 (en) 2008-10-30
WO2008130614A3 true WO2008130614A3 (en) 2008-12-24

Family

ID=39671481

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/004993 Ceased WO2008130614A2 (en) 2007-04-20 2008-04-18 Selective and dual-action p53/mdm2/mdm4 antagonists

Country Status (2)

Country Link
US (1) US8163789B2 (en)
WO (1) WO2008130614A2 (en)

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2553269C2 (en) 2009-11-12 2015-06-10 Дзе Риджентс Оф Дзе Юниверсити Оф Мичиган Spiro oxindole mdm2 antagonists
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
WO2011106650A2 (en) * 2010-02-27 2011-09-01 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Novel p53-mdm2/p53-mdm4 antagonists to treat proliferative disease
JO2998B1 (en) 2010-06-04 2016-09-05 Amgen Inc Piperidinone derivatives as mdm2 inhibitors for the treatment of cancer
CN103201263A (en) 2010-09-08 2013-07-10 匹兹堡高等教育联邦体系大学 P53-Mdm2 antagonists
FR2967072B1 (en) * 2010-11-05 2013-03-29 Univ Dundee PROCESS FOR IMPROVING INFLUENZA PRODUCTION OF VACCINE AND SEEDS
JP2014500870A (en) 2010-11-12 2014-01-16 ザ、リージェンツ、オブ、ザ、ユニバーシティ、オブ、ミシガン Spiro-oxindole MDM2 antagonist
US10822374B2 (en) 2010-11-12 2020-11-03 Dana-Farber Cancer Institute, Inc. Cancer therapies and diagnostics
JP2014513699A (en) 2011-05-11 2014-06-05 ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン Spiro-oxindole MDM2 antagonist
WO2013049250A1 (en) 2011-09-27 2013-04-04 Amgen Inc. Heterocyclic compounds as mdm2 inhibitors for the treatment of cancer
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
CN104321325B (en) 2012-05-24 2016-11-16 诺华股份有限公司 Pyrrolopyrrole alkanone compound
CA2895504A1 (en) 2012-12-20 2014-06-26 Merck Sharp & Dohme Corp. Substituted imidazopyridines as hdm2 inhibitors
US9403827B2 (en) 2013-01-22 2016-08-02 Novartis Ag Substituted purinone compounds
EP2948453B1 (en) 2013-01-22 2017-08-02 Novartis AG Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction
US11407721B2 (en) 2013-02-19 2022-08-09 Amgen Inc. CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer
CN105121407B (en) 2013-02-28 2017-07-18 美国安进公司 Benzoic acid derivative MDM2 inhibitor for treating cancer
WO2014151863A1 (en) 2013-03-14 2014-09-25 Amgen Inc. Heteroaryl acid morpholinone compounds as mdm2 inhibitors for the treatment of cancer
EP3004109A1 (en) 2013-05-27 2016-04-13 Novartis AG Imidazopyrrolidinone derivatives and their use in the treatment of disease
MX2015016421A (en) 2013-05-28 2016-03-03 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives as bet inhibitors and their use in the treatment of disease.
EA028035B1 (en) 2013-05-28 2017-09-29 Новартис Аг Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
JOP20200296A1 (en) 2013-06-10 2017-06-16 Amgen Inc Processes of Making and Crystalline Forms of a MDM2 Inhibitor
KR102092345B1 (en) 2013-09-30 2020-03-24 삼성전자주식회사 Leucine zipper variant and use thereof
WO2015075665A1 (en) 2013-11-21 2015-05-28 Novartis Ag Pyrrolopyrrolone derivatives and their use as bet inhibitors
EP3220953B1 (en) * 2014-11-21 2020-04-01 University of the Sciences in Philadelphia Compositions and methods of using therapeutic p53 peptides and analogues
KR20160126340A (en) 2015-04-23 2016-11-02 삼성전자주식회사 Three-helix bundle protein and use thereof
JP7037500B2 (en) 2016-04-06 2022-03-16 ザ リージェンツ オブ ザ ユニヴァシティ オブ ミシガン MDM2 proteolytic agent
JP7001614B2 (en) 2016-04-06 2022-02-03 ザ リージェンツ オブ ザ ユニヴァシティ オブ ミシガン Monofunctional intermediate for ligand-gated target proteolysis
CN109152843A (en) 2016-05-20 2019-01-04 豪夫迈·罗氏有限公司 PROTAC antibody conjugates and methods of using the same
CN105906610B (en) * 2016-05-24 2018-10-23 绍兴文理学院 A kind of 3-（4- phenyl -1H- imidazoles -5- bases）- 1H- indole derivatives and its preparation method and application
WO2023056069A1 (en) 2021-09-30 2023-04-06 Angiex, Inc. Degrader-antibody conjugates and methods of using same
WO2024240858A1 (en) 2023-05-23 2024-11-28 Valerio Therapeutics Protac molecules directed against dna damage repair system and uses thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANTUCH ET AL: "Design and modular parallel synthesis of a MCR derived alpha-helix mimetic protein-protein interaction inhibitor scaffold", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 16, no. 6, 15 March 2006 (2006-03-15), pages 1740 - 1743, XP005280789, ISSN: 0960-894X *
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Also Published As

Publication number Publication date
WO2008130614A2 (en) 2008-10-30
US8163789B2 (en) 2012-04-24
US20080280769A1 (en) 2008-11-13

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